This present invention relates to biodegradable radio-opaque compounds that can be used as contrast agents in medical imaging, surgical markers and for localized drug delivery. The invention also relates to radio-opaque compounds, compositions containing such compounds and methods of their synthesis and use.
Definitions:
All scientific and technical terms used herein have the same meaning as is commonly understood by one skilled in the synthetic polymer chemistry, polyethylene glycol modification chemistry, controlled drug delivery and synthetic biodegradable chemistry art, and to which this invention belongs; unless it is defined specifically for this invention.
“Oligomers” are defined as low molecular weight polymeric compounds. In this invention, oligomers may be defined as polymeric compounds with molecular weight between 40-2000 Daltons.
“Cross-linked material” is meant to denote the conversion of a soluble material to an insoluble state. The crosslinked material may still be in a highly hydrated state.
“In situ” is meant to denote at a local site, especially within or in contact with living organisms, tissue, organs, or the body.
“Bioactive” as used herein, refers to one or all of the activities of a compound that show pharmacological or biological activity in human or animal body. Such biological activity is preferred to have therapeutic effect. The bioactive compounds that can be used include, but not limited to: antiviral agents; antiinfectives such as antibiotics; antipruritics; antipsychotics; cholesterol or lipid reducing agents, cell cycle inhibitors, anticancer agents, antiparkinsonism drugs, HMG-CoA inhibitors, antirestenosis agents, antiinflammatory agents; antiasthmatic agents; antihelmintics; immunosuppressives; muscle relaxants; antidiuretic agents; vasodilators; nitric oxide, nitric oxide releasing compounds, beta-blockers; hormones; antidepressants; decongestants; calcium channel blockers; growth factors such as bone growth factors, wound healing agents, analgesics and analgesic combinations; local anesthetics agents, antihistamines; sedatives; angiogenesis promoting agents; angiogenesis inhibiting agents; tranquilizers and the like. Cellular elements which be used for therapeutic use such as mammalian cells including stem cells, cellular components or fragments, enzymes, DNA, RNA, genes may also be included as bioactive components.
“Biodegradable” is meant to denote a material that will degrade in a biological environment by either a biologically assisted mechanism, such as an enzyme catalyzed reaction or by a chemical mechanism which can occur in a biological medium, such as hydrolysis.
“Biostable” is meant to denote a high chemical stability of a compound in an aqueous environment, which is similar to the environment, found in the human body such as phosphate buffered saline (pH 7.2).
“Injectable composition” means any polymeric or non-polymeric composition that can be injected as a liquid and converted into solid inside a human body using minimally invasive surgical devices.
Polyethylene glycol (PEG) or polyethylene oxide (PEO) refers to the same polymer which is made by polymerization of ethylene oxide.
Polymeric nomenclature used in this patent application such as poly (lactic acid) or polylactic acid or polylacticacid refer to the same polymer, unless otherwise stated clearly. This is also true for all others polymers referred in this patent application.
The radio-opaque nature of many compounds allows them to be traced within a human or an animal body and therefore such compounds find application in medical diagnostics and pharmaceutical field. Some of the applications of such radio opaque compounds include medical imaging applications such as x-rays, angiography, urography, phlebography and drug delivery at a localized site.
In medical imaging techniques such as X-ray imaging, attenuation of soft tissue by x-ray radiation can be improved by exogenously administering a radio-opaque compound, which gets distributed in the tissue to be imaged. The infused compound preferentially absorbs x-ray radiation in the tissue and therefore improves quality of the image. Such improved image results in better diagnosis of the medical condition.
It is desired that such compounds should mix with the body fluids without causing significant change in the local chemical environment such as osmolarity, which is concentration of the solute per unit of total volume of solution and pH, should be economically feasible, chemically stable, highly water soluble, readily injectable with low viscosity and a ready to inject solution, biologically inert and should be removable safely and completely by the body.
The radio opaque compounds reported in the prior art generally fall into two categories: ionic and non-ionic. The ionic monomeric compounds used as contrast media for intravascular use have an osmolarity seven to eight times that of normal human blood. This hyper-osmolarity is partly believed to be responsible for several subjective and objective adverse effects such as pain, endothelial damage, thrombosis and thrombophlebitis, disturbance of the blood-brain barrier, bradycardia in cardioangiography and increased pressure in the pulmonary circulation. On the other hand, non-ionic compounds such as Iohexol, Iopamidol, metrizamide are formulated as less hyperosmolar solutions. However, the current non-ionic radio opaque compounds are much more expensive and exhibit relatively high rate of adverse events. In a recent small clinical study, two non-ionic media containing Iohexol and Ioversol were compared. More than 10% patients, receiving either Iohexol or Ioversol reported adverse events, which were categorized from mild to moderate to severe. These events included dizziness, pruritus, apnea, fever, purpura, blurred vision, headache, urticaria, congestion, lightheadedness, vertigo, cough, metallic taste, disorientation, and nausea. Hence, the side effects of these ionic as well as non-ionic contrast agents cannot be overruled.
U.S. Pat. No. 5,746,998 titled “Targeted co-polymers for radiographic imaging” describes polymeric compounds such as diblock copolymers capable of forming micelles for medical imaging. The block copolymers, a combination of two polymers, and high molecular weight are essential to form micelles. Such polymers require several multistep synthesis procedures. In addition, water soluble biologically intert polymers such as polyethylene oxide or poly (vinyl pyrrolidinone), with molecular weight above 20,000 g/mol are not eliminated by the body and therefore are stored inside the body. Thus high molecular weight polymers above 20,000 are considered as non-degradable permanent implants. On the other hand, polyethylene glycol with a molecular weight below 300 is insoluble in water. Water solubility is considered essential for safe removal of the compound. Many derivatives of polyethylene oxide such as polyethylene glycol succinate based derivatives, glutaric acid based derivatives and hydroxy acid based derivatives undergo substantial hydrolysis and degradation when stored in water for prolonged periods of time. Such degradation leads to unstable formulations and may have toxic effects on the human body.
Also, ionized polymers used for medical imaging applications can increase the osmolarity of the injectable solution with their counter ions. This may lead to several adverse effects as pain, endothelial damage, and the like. For example, polylysine is considered as a charged polymer and must be ionized to bring its pH to physiological range.
In addition, polyethylene glycol (PEG) based compounds used for these applications are also susceptible for oxidative reaction, which can form toxic peroxide radicals. These PEG based compounds must be combined with antioxidants to improve shelf life and prevent oxidative related reactions.
Along with medical imaging, some of the radio-opaque polymers that are biodegradable have received considerable interest in the medical and pharmaceutical field, as they can perform temporary therapeutic function and are eliminated from the body once the therapeutic function has been accomplished. Some of the well-known applications of biodegradable polymers include surgical sutures, staples or other wound closure devices, as a carrier for bioactive substances for controlled drug delivery etc. Among the biodegradable polymers reported in the prior art, polymers prepared from hydroxy acids and/or polylactones have received much attention due to their degradability and toxicological safety. Homopolymers and copolymers based on the l-lactic acid, dl-lactic acid and glycolic acid are among the most widely used polymers for medical applications. These polymers can be formulated into variety of physical forms such as fibers or filaments with acceptable mechanical properties, degradation profile and non-toxic degradation products.
To visualize the deployment of bioabsorbable implantable devices in the human or animal body, many surgical procedures are performed with the aid of fluoroscopic angiography. However, most biodegradable polymers used in current clinical practice have poor visibility when viewed using standard medical imaging equipment. The absorbable polymeric material may be visualized if they are radio-opaque and offer radiographic contrast relative to the body. To make the absorbable polymer radio-opaque, it must be made from a material possessing radiographic density higher than surrounding host tissue, and have sufficient thickness to affect the transmission of radiations and produce a contrast in the image. To improve the visualization, the biodegradable polymer must be chemically and physically modified.
U.S. Pat. No. 6,174,330 titled “Bioabsorbable marker having radio-opaque constituents” discloses use of bioabsorbable polymer mixed with non-absorbable radio-opaque moieties such as heavy metal compounds mixed with the absorbable polymer. U.S. Pat. No. 6,475,477 titled “Radio-opaque polymer biomaterials” discloses tyrosine derived radio-opaque polymers.
However, current technologies may not be able provide radio-opaque biodegradable polymers that are degraded and completely eliminated by the body and also have good visibility when administered in a human or an animal body.
The above-mentioned limitation linked to biodegradable radio-opaque polymers is also applicable to Minimal Invasive Surgery (MIS) techniques. Minimally invasive surgery (MIS) encompasses laparoscopy, thoracoscopy, arthroscopy, intraluminal endoscopy, endovascular techniques; catheter based cardiac techniques such as balloon angioplasty, interventional radiology and the like. These procedures allow mechanical access to the interior of the body with the least possible perturbation of the patient's body. Many MIS procedures involve very small mechanical tools such as catheters or trocars that are manipulated outside the patient's body but are capable of performing their function within the patient's body. Biodegradable polymers that can be used with MIS procedures are becoming increasingly important. These polymers are used as sutures, surgical clips, staples, sealants, tissue coatings, implants and drug delivery systems. The polymers that are used with MIS applications are either preformed or are generated in-situ. However, the visibility of these polymers when administered in a human or an animal body is low. In many MIS applications, it is essential to transport the material at the surgical site. The radio-opacity helps to monitor the movement of implant from the site of implantation or degradation of implant. Radio-opacity also helps to locate and retrieved the biodegradable implant if necessary. Thus radio-opacity offers many useful functionalities, which may help to offer better medical treatments.
A need exists for radio-opaque polymers that are easily degraded in the body and have no side effects. There is also a need of polymers that have a good visibility under medical imaging scanners. There is further a need for injectable biodegradable polymeric compositions that are radio-opaque and can be used to deliver bioactive drugs using MIS techniques.